Despite the dramatic success of highly active antiretroviral therapy (HAART) in inhibiting viral replication in HIV-infected subjects, it is increasingly clear that there is a compelling rationale for the development of complementary therapies, most notably genetic therapies for HIV disease. Recent experiments from the Prasad laboratory have demonstrated quite potent inhibition of HIV-1 and RT-SHIV replication by RT-specific aptamers. Aptamers have a number of distinctive advantages as a modality to inhibit HIV replication, including the ability to target multiple elements of the retroviral life cycle, their relative resistance to the emergence of escape viruses, and their observed potency in inhibiting HIV replication. Experiments in this project will focus on examining the effect of HIV-specific aptamers in inhibiting SHIV replication in vitro and in nonhuman primates that receive genetically-modified CD4+ T cells or CD34+ bone marrow cells. Specific aims include: 1) To examine the ability of HIV-specific aptamers to inhibit SHIV replication in primary CD4+ T cells derived from peripheral blood and from transduced rhesus CD34+ cells in vitro. 2) To examine the ability of HIV-specific aptamers to inhibit SHIV replication in genetically-modified CD4+ T lymphocytes in vivo. 3) To examine levels of gene marking in uninfected macaques transplanted with hematopoietic stem cells transduced with vectors expressing HIV-specific aptamers. 4) To examine the ability of HIV-specific aptamers to protect hematopoietic cells from SHIV infection in vivo. These studies should yield important information regarding the efficacy and safety of aptamer-based stem cell gene therapy for AIDS and ultimately facilitate the development of similar trials in HIV-infected people.